The use of alpha, beta or gamma cyclodextrins as cage molecules capable of trapping hydrophobic molecules has been particularly well described: trapping of vitamin E (Japanese patent JP56/139409), vitamin D3 (JP52/130904) for example, but also menthol, fragrances, essential oils, etc.
However, the use of such cyclodextrins poses a certain number of problems: in particular, their solubility in an aqueous phase is very poor (in particular beta cyclodextrin) and their solubility in a hydrophobic phase is almost zero. Faced with such a problem, a first strategy consists of producing derivatives of such cyclodextrins to increase the solubility of the molecules in aqueous phases:
using methyl, dimethyl, polymethyl derivatives,
using hydroxyalkylated derivatives (European patent EP-A1-0 636 634),
using sulfate or phosphate derivatives,
or to increase their solubility in oily phases:
using lipophilic derivatives (U.S. Pat. No. 3,565,887),
using lipophilic hydroxyalkylated derivatives (EP-A1-0 773 229),
using cyclodextrins monosubstituted exclusively on their primary face (reaction with a primary alcohol function) or cyclodextrins completely substituted exclusively on their secondary face (reaction with all of the secondary alcohol functions) (French patent FR-A-2 681 868).
Further, a second strategy has slowly been developing in which amphiphilic structures are synthesized from cyclodextrins, which structures enable the cyclodextrins to arrange themselves into micelles or nanoparticles:
the products described in French patent FR-A-2 681 868 can thus form nanoparticles,
the products described in European patent EP-A-0 773 229 can form nanoparticles,
it is also possible to produce the nanoparticies which are described in International patent application WO 93/25194 from cyclodextrins completely substituted on their secondary face, synthesized in accordance with Zhang and al. (Zhang, Ling, Coleman, Parrot-Lopez, Galons, Tetrahedron Letters 32 (24) 2769-2770, 1991).
The inventors have unexpectedly discovered that, in contrast to current wisdom, it is possible to produce nanoparticles from amphiphilic cyclodextrins which are mono- or multi-substituted, preferably on their primary face.
The skilled person will always aim to substitute the secondary face of cyclodextrins to produce nanoparticles, as the geometry of nanoparticles substituted on their secondary face is highly favorable to the formation of curved shapes (which enable such structures to organize themselves into nanoparticles), while the geometry of cyclodextrins substituted on their primary face is highly unfavorable to the formation of nanoparticles. Thus amphiphilic cyclodextrins for the production of nanoparticles are synthesized by blocking the primary alcohol functions which are chemically more reactive, then alkylating the secondary alcohol functions, and unblocking the primary alcohol functions in a third stage (Zhang et al., 1991 and also FR-A-2 681 868 and EP-A-0 773 229). This sequence of reactions causes problems with yield and with the industrialization of processes, which limits their use. Commercial use is currently non-existent.
The inventors have succeeded in producing nanoparticles from non-hydroxyalkylated cyclodextrins, mono- or di-substituted on their primary face which was completely unexpected, with many fields of application in the areas of encapsulating molecules of cosmetic, pharmaceutical, or agro-industrial interest, and of modulating the penetration of encapsulated active ingredients into tissues, cells, etc. . . .
The inventors have also discovered that the amphiphilic cyclodextrins of the invention have the capacity to promote penetration of active ingredients in a manner which is spectacularly stronger than other vectors which have been far more widely studied, namely liposomes.
For this reason, the targeting properties of these amphiphilic cyclodextrin molecules (which may or may not be in the form of nanoparticles, included in phospholipid double layers or not) have become extremely interesting, and chemical modifications of these cyclodextrins have been made to allow such targeting.
In particular, the invention enables molecules with selective affinities to be grafted onto the amphiphilic cyclodextrins of the invention, via a spacer arm which may or may not remain present in the chemical structure of the molecule formed.
The invention also renders possible the production of completely novel chemical entities of real industrial and economic significance in fields as varied as cosmetics, pharmacy, agro-industry, etc. . . .
Thus a principal aim of the invention is to solve the novel technical problem consisting of providing novel chemical entities which can be used in cosmetics, pharmacy, agro-industry and in the food industry.
A further principal aim of the present invention is to solve a novel technical problem consisting of providing a solution which can provide novel chemical cyclodextrin entities which can form nanoparticles or micelles of very small dimensions, in particular nanoparticles.
A still further principal aim of the present invention is to solve the novel technical problem consisting of providing novel chemical cyclodextrin entities which are easy to synthesize and have a good synthesis yield, thus enabling such novel chemical entities to be used on an industrial scale.
A yet still further principal aim of the present invention is to solve the novel technical problem consisting of providing novel chemical cyclodextrin entities which can trap or encapsulate molecules of cosmetic, pharmaceutical or agro-industrial interest to enable the penetration of the encapsulated active ingredients into tissue, cells etc. to be modulated.
A yet still further principal aim of the present invention is to solve the novel technical problem consisting of providing a solution which can provide novel chemical cyclodextrin entities with the capacity to promote penetration of active ingredients in a manner which is spectacularly stronger than other vectors which have been more widely studied, namely liposomes.
A yet still further principal aim of the present invention is to solve the novel technical problem consisting of providing novel chemical cyclodextrin entities which can graft molecules with selective affinities directly or via a spacer arm which remains in the chemical structure of the molecule thus formed.
All of these technical problems are solved for the first time by the present invention in a particularly simple fashion, with excellent yields, rendering the solution of the invention useful on an industrial and on a commercial scale, in fields as varied as the cosmetics industry, in pharmacy, in the agro-industry and in the food industry.
Thus in a first aspect, the invention concerns the use of non-hydroxyalkylated cyclodextrins wherein at least one primary alcohol function (CH2OH) is substituted, the xe2x80x94OH portion being replaced by a substituent with formula xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94R or xe2x80x94NR1R2, where:
R, R1 and R2 independently represent a linear or cyclic, saturated or unsaturated, hydroxylated or non-hydroxylated hydrocarbon radical containing 1 to 30 carbon atoms, preferably 1 to 22 carbon atoms, more preferably a fatty chain 2 to 22 carbon atoms;
to encourage tissue penetration, either for a cosmetic application or for producing pharmaceutical compositions, in particular dermopharmaceutical compositions; provided that when the substituent has formula xe2x80x94Oxe2x80x94COxe2x80x94R, the esterified non-hydroxyalkylated cyclodextrins are used as a vector for at least one active ingredient.
In a second aspect, the present invention concerns the use of non-hydroxyalkylated cyclodextrins in the form of micelles or nanoparticles, wherein at least one primary alcohol function (CH2OH) is substituted, the xe2x80x94OH portion being replaced by a substituent with formula xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94R or xe2x80x94NR1R2, where:
R, R1 and R2 independently represent a linear or cyclic, saturated or unsaturated, hydroxylated or non-hydroxylated hydrocarbon radical containing 1 to 30 carbon atoms, preferably 1 to 22 carbon atoms, more preferably a fatty chain 2 to 22 carbon atoms;
to encourage tissue penetration, either for a cosmetic application or for producing pharmaceutical compositions, in particular dermopharmaceutical compositions, preferably as a vector for at least one active ingredient.
It should be noted that cyclodextrins have primary alcohols on their primary face defined by the short base of their trapezoidal shape, and secondary alcohol functions on their secondary face defined by the long base of said trapezoid (conventional structure of cyclodextrin). The invention preferably produces substitution on the primary alcohol functions of the primary face of the cyclodextrins. The skilled person will know that each glucose unit of a cyclodextrin comprises two secondary alcohols and one primary alcohol.
Advantageously, the substituted cyclodextrin has the following chemical formula:
CD(OH)w(P)x(X)y(M)z
where:
CD represents a structure based on a non-hydroxyalkylated cyclodextrin without its hydroxyl groups, in particular xcex1, xcex2 or xcex3-cyclodextrin,
OH represents the free hydroxyl groups of the cyclodextrin,
x and z independently represent a whole number in the range 0 to 17, or in the range 0 to 20, or in the range 0 to 23, when the cyclodextrins are respectively xcex1, xcex2 or xcex3 in type;
y represents a whole number in the range 1 to 18, or in the range 1 to 21, or in the range 1 to 24 when the cyclodextrins are respectively xcex1, xcex2 or xcex3 in type,
w represents a whole number such that the sum (w+x+y+z) is equal to 18, 21 or 24 when the cyclodextrins are respectively xcex1, xcex2 or xcex3 in type;
X represents a substituent with formula xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94R or xe2x80x94N(R1R2) defined below, replacing the xe2x80x94OH portion of at least one primary alcohol function and optionally at least one secondary alcohol function;
P represents a radical substituting a primary or secondary hydroxyl group, in particular a sulfate, phosphate, methyl, ose or oside substituent;
when at least one X represents xe2x80x94NR1R2, xe2x80x94NR1R2 is a radical substituting at least one primary hydroxyl group and optionally at least one secondary hydroxyl group, or the two, attached to the cyclodextrin skeleton, where R1 and R2 independently represent a linear or cyclic, saturated or unsaturated, hydroxylated or non-hydroxylated hydrocarbon radical containing 1 to 30 carbon atoms, preferably 1 to 22 carbon atoms, more preferably a fatty chain 2 to 22 carbon atoms; preferably when X represents NR1R2, 1% to 100% of the primary cyclodextrin hydroxyl groups are substituted by the amino group NR1R2;
when at least one X represents xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94R, xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94R is a radical substituting at least one primary hydroxyl group, and optionally at least one secondary hydroxyl group, or the two, attached to the cyclodextrin skeleton, where R represents a linear or cyclic, saturated or unsaturated, hydroxylated or non-hydroxylated hydrocarbon radical containing 1 to 30 carbon atoms, preferably 1 to 22 carbon atoms, more preferably a fatty chain containing 2 to 22 carbon atoms; preferably, when X represents xe2x80x94Oxe2x80x94COR, 1% to 100% of the primary hydroxyl groups of the cyclodextrins are substituted by the ester group xe2x80x94Oxe2x80x94COR;
(X)y can represent mixtures of xe2x80x94NR1R2 or xe2x80x94OCOR groups substituting at least one primary hydroxyl group and optionally at least one secondary hydroxyl group, or the two;
M is a substituent for at least one primary or secondary alcohol function or the two of the cyclodextrin, M is a functional group G1 or a specific radical G2, either directly substituting a primary or secondary alcohol function of the cyclodextrin, or indirectly substituting said primary or secondary alcohol function via a spacer arm W, where:
W is a spacer arm containing 1 to 20 carbon atoms, including the groups selected from the following functions and their derivatives: acid, sulfonic and phosphoric acid, alkanoyl, alkenyl, alkynyl, aldehyde, amine, amide, azide, acid anhydride, ketone, isocyanate, phenyl, hydroxyl, epoxy, ester, imide, amidine, halide, nitro, nitrites, peroxides, organometallic derivatives, sulfur-containing derivatives;
G1 represents at least one of the following functions and its derivatives: acid, sulfonic and phosphoric acid, alkanoyl, alkenyl, alkynyl, aldehyde, amine, amide, azide, acid anhydride, ketone, isocyanate, phenyl, hydroxyl, epoxy, ester, imide, amidine, halide, nitro, nitrites, peroxides, organometallic derivatives, sulfur-containing derivatives; and
G2 represents at least one of the following compounds or its derivatives selected from the group consisting of a sugar, a polyol, an oligosaccharide, a polysaccharide, a lectin, an amino acid, a peptide, a protein, an antibody, a nucleotide, a nucleoside, an oligonucleotide, an oligonucleoside, a chromophore, a polymer, a sterol, a steroid, a hormone, a flavonoid, a terpene, caffeine, theophylline and their derivatives, nicotine and its derivatives, a vitamin, a vitamin ester, cholesterol, a phospholipid, a glycolipid, a sphingolipid, a ceramid, a triglyceride, a natural or synthetic polyphenol, an essential oil, a flavoring, a fragrance, a dye, or a cosmetically, dermopharmaceutically, pharmaceutically or alimentarily active substance.
In the present description and claims, the expression:
xe2x80x9ca substituent of at least one primary or secondary alcohol functionxe2x80x9d means substitution of either a primary alcohol group carried by a primary alcohol function xe2x80x94CH2OH, or of a secondary alcohol group carried by the secondary alcohol function xe2x80x94CHOH, as is well understood by the skilled person,
xe2x80x9cat least one primary or secondary hydroxyl functionxe2x80x9d means a primary or secondary hydroxyl function present in a primary alcohol function xe2x80x94CH2OH or a secondary alcohol function xe2x80x94CHOH attached respectively to the cyclodextrin skeleton.
In a particular embodiment, said cyclodextrin is a cyclodextrin substituted by 1 to 18, 1 to 21 or 1 to 24 lauric fatty chains when the cyclodextrins are respectively type xcex1, xcex2 or xcex3, in particular 2 or 3 lauric chains, or 7, 8 or 9 lauric chains.
In a particular embodiment, the above cyclodextrin derivative is a cyclodextrin substituted by at least one hexanoyl substituent on at least one primary hydroxyl function, in other words a cyclodextrin substituted by 1 to 18, 1 to 21 or 1 to 24 fatty hexanoic chains when the cyclodextrins are respectively type xcex1, xcex2 or xcex3, in particular 6 to 10 hexanoic chains, principally 7, 8 and 9 hexanoic acid chains.
A further particular embodiment is constituted by a substituted cyclodextrin wherein at least one primary hydroxyl function is substituted by at least one N,N-dipentylamine group.
In yet another particular embodiment of the invention, the cyclodextrin derivative is further substituted by at least one substituent selected from the group formed by 4-nitrophenylformate; ethyloxalic; chloroacetyl; succinic; oxalic sulfonic; N-(2-aminoethyl)lactonamide.
In yet another particular embodiment, the cyclodextrin derivative is a xcex2-cyclodextrin, in particular a heptakis (6-deoxy-6-(N,N-dipentylamino))-xcex2-cyclodextrin.
In yet another advantageous embodiment, said cyclodextrin comprises at least one primary or secondary hydroxyl flinction substituted by a functional group G1 or a radical G2 as cited above selected from the following compounds or functions or their derivatives selected from the group formed by acid, sulfonic and phosphoric acid, alkanoyl, alkenyl, alkynyl, aldehyde, amine, amide, azide, an anhydride, ketone, isocyanate, phenyl, hydroxyl, epoxy, ester, imide, amidine, halide, nitro, nitriles, peroxides, organometallic derivatives, sulfur-containing derivatives, a sugar, an oligosaccharide, a polysaccharide, an amino acid, a peptide, a protein, a nucleotide, an oligonucleotide, a nucleoside, an oligonucleoside, a chromophore, a polymer, a steroid, a vitamin or another active ingredient.
In a yet still further particularly advantageous embodiment, the cavity of the substituted cyclodextrin comprises an active ingredient which is in particular cosmetically, dermopharmaceutically, pharmaceutically, or alimentarily acceptable, encapsulated therein and/or covalently bonded therewith.
In an advantageous characteristic of the invention, the active ingredient is selected from the group formed by at least one sugar, a polyol, an oligosaccharide, a polysaccharide, an amino acid, a peptide, a protein, a nucleotide, a nucleoside, an oligonucleotide, an oligonucleoside, a chromophore, a polymer, a sterol, a steroid, a hormone, a flavonoid, a terpene, caffeine, theophylline and their derivatives, nicotine and its derivatives, a vitamin, a vitamin ester, cholesterol, a phospholipid, a glycolipid, a sphingolipid, a ceramid, a triglyceride, a natural or synthetic polyphenol, an essential oil, a flavoring, a fragrance, a dye, or a cosmetically, dermopharmaceutically, pharmaceutically, or alimentarily acceptable excipient.
In a further particular embodiment of the invention, said cyclodextrin comprises at least a second graft, in which said functional group G1 or said radical G2, directly or indirectly substituting the primary or secondary alcohol function, is different from that possibly used for the first graft. Particular examples of at least one second graft are a second graft on at least one alcohol function of the primary face of the cyclodextrin molecule and/or on at least one alcohol function of the secondary face of the cyclodextrin molecule, selected from the group formed by:
one or more 4-nitrophenylformate groups;
one or more ethyloxalic groups;
one or more chloroacetyl groups;
one or more succinic acid groups;
one or more oxalic acid groups;
one or more sulfonic acid groups;
one or more ethylene diamine groups;
one or more lactone groups, in particular N-(2-amino ethyl)lactonamide.
In a third aspect, the present invention encompasses micelles or nanoparticles based on cyclodextrin derivatives, wherein they are prepared from a non-hydroxyalkylated cyclodextrin derivative as defined above or as described in the following description including the examples, supplemented by the figures, which in their generality form an integral part of the present invention.
The characteristic advantages of micelles or nanoparticles are defined in the sub-claims which are incorporated into the description by reference.
In a fourth aspect, the present invention encompasses a composition selected from the group formed by a cosmetic, dermopharmaceutical, pharmaceutical or agro-alimentary composition, wherein the composition comprises at least one cyclodextrin, in particular in the form of micelles or de nanoparticles, as defined above or as described in the following description as a whole and including the examples supplemented by the figures, in combination with a cosmetically, dermopharmaceutically or pharmaceutically acceptable excipient, vehicle or support or an excipient, vehicle or support which is alimentarily acceptable, this excipient being in particular composed of phospholipids, for example lecithin, surfactants or cationic lipids.
In a fifth aspect, the invention encompasses a composition selected from the group formed by a cosmetic, dermopharmaceutical, pharmaceutical or agro-alimentary composition, wherein the composition comprises at least one micelle or nanoparticle as defined above or resulting from the following description including the examples supplemented by the figures, in combination with a cosmetically, dermopharmaceutically or pharmaceutically acceptable excipient, vehicle or support or an excipient, vehicle or support which is alimentarily acceptable, this excipient being in particular composed of phospholipids, for example lecithin, surfactants or cationic lipids.
The advantageous characteristics of these compositions are also shown in the composition sub-claims which are entirely incorporated into the description by reference.
In a sixth aspect, the present invention encompasses cyclodextrin derivatives as defined above which are novel with respect to any prior art. In particular, cyclodextrin derivatives in which:
either at least one X represents xe2x80x94N(R1R2) of a primary alcohol;
or at least one X represents xe2x80x94N(R1R2) combined with at least one xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94R;
or at least one X represents xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94R with at least one radical P and/or at least one radical M substituting at least one primary alcohol and/or secondary alcohol; are novel and are claimed as such.
A preferred group of novel cyclodextrin derivatives is constituted by cyclodextrin derivatives in which at least one substituent P or M is present.
Still more preferred derivatives are those in which, in addition to the primary hydroxyl function substituted as defined in the present description and claims, at least one secondary hydroxyl function is substituted by at least one substituent P or M as defined in the present description and claims.
Cyclodextrin derivatives in which the substituted cyclodextrin cavity comprises an active ingredient, in particular cosmetically, dermopharmaceutically, pharmaceutically or alimentarily acceptable, encapsulated therein and/or covalently bonded thereto, also constitute novel cyclodextrin derivatives claimed as they are. Examples of active ingredients as defined in the present description and claims are also claimed as forming an integral portion of the present invention.
In a seventh aspect, the present invention still further encompasses a process for producing novel cyclodextrin derivatives as defined above, wherein the process comprises the following synthesis steps, preferably in succession:
a) firstly, substituting at least one primary hydroxyl function of a cyclodextrin by a chemical molecule capable of providing a substituent with formula xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94R or xe2x80x94NR1R2, having the meanings defined in the present description and claims;
b) optionally, substituting at least one primary or secondary hydroxyl function or both with a radical M or P as defined in the present description and claims.
In an advantageous implementation of this process, when a substituent radical P is present, at least one primary or secondary hydroxyl group is substituted by a sulfate, phosphate, methyl, ose or oside substituent.
The term xe2x80x9cose or osidexe2x80x9d as used in the present invention means the entire family of oses or osides, which are well known to the skilled person, in particular sugars, oligosaccharides, polysaccharides, nucleotides, nucleosides, oligonucleotides, and oligonucleosides.
The reaction conditions are well known to the skilled person.
As an example, the reaction conditions of U.S. Pat. No. 3,565,887 can be applied to prepare cyclodextrin derivatives with esterified primary alcohol functions.
It is also possible to apply the reaction conditions defined for cyclodextrin substitution described in FR-A-2 680 868 or EP-A-0 773 229 or WO-A-93/25194.
Further reaction conditions will also be made clear in the examples and description below.
In an eighth aspect, the invention encompasses a process for producing micelles or nanoparticles comprising cyclodextrin derivatives of the present invention, as defined above or resulting from the following description incorporating the examples supplemented by the figures, wherein the process comprises an organic phase into which the substituted cyclodextrins are introduced and a principally aqueous phase. These two phases are mixed under controlled flow rate, stirring and temperature parameters. Stirring can be either mechanical or sonic.
In a ninth aspect, the present invention also encompasses a cosmetic care method, wherein a cosmetically effective quantity of at least one cyclodextrin derivative as defined above in the context of any one of its aspects or as resulting from the following description made with reference to the examples, optionally in a cosmetically acceptable excipient, is applied to a zone of the body of a person requiring the care.
In the context of this cosmetic care, the cyclodextrin derivatives unexpectedly encourages cutaneous penetration, in a manner which is improved over liposomes.
In a tenth aspect, the invention encompasses a therapeutic treatment method wherein a pharmaceutically effective quantity of at least one cyclodextrin derivative as defined in the present invention in any one of its aspects, optionally in a pharmaceutically acceptable excipient, is administered to a patient. In the context of this therapeutic treatment, it should be clear that the cyclodextrins of the invention can improve the bioavailability of the pharmaceutically active substances encapsulated by said substituted cyclodextrins or covalently contained by them.